There is a vital need for effective treatments against seizure-related brain damage and other events of excitotoxic neurodegeneration. Recurring seizures can result from epilepsy, brain trauma, developmental disorders, exposure to toxins, military-threat agents, and drugs of abuse (including prenatal exposure). Seizure-induced damage involves the same excitotoxic over-activation of glutamate receptors as occurs in stroke and traumatic brain injury. The resulting brain damage can cause devastating neurological, cognitive, and neuropsychiatric problems. With the need to find better therapeutic avenues, this proposal will further develop drugs to enhance the neuroprotective activation of the endocannabinoid system that occurs in response to excitotoxic insults including seizures. Compensatory synthesis and release of endogenous anandamide have been linked to excitotoxic protection in the brain. Our SBIR Phase-I work identified novel inhibitors of the endocannabinoid-hydrolyzing enzyme fatty acid amide hydrolase (FAAH) that effectively reduced seizure severity as well as the associated brain damage and behavioral deficits, even when administered several hours post-insult. This Phase-II proposal will continue to take advantage of the convenient KA rat model of seizure induction in order to facilitate the timely assessment of new, "drugable" FAAH inhibitor analogs with improved physicochemical and pharmacological profiles. The overall goal is to generate one potential candidate and three back-ups as selective, potent, and safe neuroprotectants for development as first-in-class drugs for treating seizure-related damage and other types of excitotoxic insults that cause long-term neurological impairment. PUBLIC HEALTH RELEVANCE: Successful development of medications to treat diseases whose etiology involves excitotoxic brain injury and its symptoms (particularly, seizures) will satisfy pressing medical needs for various disorders (stroke;Alzheimer's, Huntington's, and Parkinson's diseases;amyotrophic lateral sclerosis) for which extant therapies offer marginal value. Drugs of abuse may act as neurotoxicants and incite excitotoxic brain injury and seizures, and their neurodegenerative effects can adversely affect the developing fetus in utero. The latter is of particular importance to NIDA's mission. Our overall goal is to generate one potential development candidate and three back-ups to address the therapeutic needs of these disorders.